Inhibitor of Apoptosis (IAP) proteins are commonly over-expressed in human tumors and thereby contribute to tumor cell survival. As a result, IAPs have become attractive drug targets in cancer therapy. Several small molecules targeting IAPs are in clinical trials. The design of these compounds is based on a short IAP-binding motif (IBM) that is present in natural IAP-antagonists, such as Drosophila Reaper/Hid/Grim and mammalian Smac. Derivatives of the Hid IBM have proven most effective. They are reviewed in Vaux, D. L. (2009). Biology Reports 1:79, the contents of which are incorporated herein by reference. Although these IBM-mimetics show some promise, they have some serious limitations. In particular, all available compounds primarily target cIAP1/2, but are poor inhibitors of XIAP. Improved targeting of XIAP would be desirable, since this protein is a potent cell death inhibitor that is over-expressed in human tumors. It has been shown that inactivation of XIAP protects against tumorigenesis in the mouse, and that loss of the XIAP-antagonist ARTS causes increased malignancies [Schile et al., (2008) Genes Dev. 22, 2256-2266; Garcia-Fernandez et al., (2010) Genes Dev. 24, 2282-2293]. We now disclose that using a “generic” mitochondrial targeting sequence to direct a short IBM-peptide to the mitochondrial outer membrane is sufficient for potent inhibition of XIAP and selective killing of human cancer cell lines.